NM_004431.5:c.824-2999C>A

Variant names:

• chr1-16141429-G-T
• rs3768293
• NM_004431.5:c.824-2999C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004431.5(EPHA2):​c.824-2999C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 152,172 control chromosomes in the GnomAD database, including 25,673 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.57 (25673 hom., cov: 34)
• Consequence: EPHA2 NM_004431.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.793
• Publications: 12 publications found

Genes affected

EPHA2 (HGNC:3386): (EPH receptor A2) This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. This gene encodes a protein that binds ephrin-A ligands. Mutations in this gene are the cause of certain genetically-related cataract disorders.[provided by RefSeq, May 2010]

EPHA2 Gene-Disease associations (from GenCC):

• cataract 6 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• early-onset non-syndromic cataract

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior subcapsular cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.842 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004431.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	NM_004431.5	MANE Select	c.824-2999C>A		intron	N/A	NP_004422.2
	EPHA2	NM_001329090.2		c.662-2999C>A		intron	N/A	NP_001316019.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	ENST00000358432.8	TSL:1 MANE Select	c.824-2999C>A		intron	N/A	ENSP00000351209.5
	EPHA2	ENST00000480202.1	TSL:5	n.29-2999C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87278 AN: 152054 Hom.: 25664 Cov.: 34

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.525

Gnomad EAS AF: 0.863

Gnomad SAS AF: 0.568

Gnomad FIN AF: 0.675

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.557

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.574 AC: 87322 AN: 152172 Hom.: 25673 Cov.: 34 AF XY: 0.577 AC XY: 42904 AN XY: 74396

African (AFR) AF: 0.476 AC: 19761 AN: 41498

American (AMR) AF: 0.568 AC: 8690 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.525 AC: 1821 AN: 3468

East Asian (EAS) AF: 0.863 AC: 4471 AN: 5180

South Asian (SAS) AF: 0.569 AC: 2748 AN: 4826

European-Finnish (FIN) AF: 0.675 AC: 7154 AN: 10594

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.600 AC: 40787 AN: 67986

Other (OTH) AF: 0.554 AC: 1171 AN: 2114

Alfa AF: 0.587 Hom.: 43299

Bravo AF: 0.568

Asia WGS AF: 0.667 AC: 2321 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.22
DANN	Benign	0.58
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3768293; hg19: chr1-16467924;